Thermally cross-linkable photo-hydrolyzable inkjet printable polymers for microfluidic channels

ABSTRACT

Thermally cross-linkable photo-hydrolyzable inkjet printable polymers are used to print microfluidic channels layer-by-layer on a substrate. In one embodiment, for each layer, an inkjet head deposits droplets of a mixture of hydrophobic polymer and cross-linking agent in a pattern lying outside a two-dimensional layout of the channels, and another inkjet head deposits droplets of a mixture of poly(tetrahydropyranyl methacrylate) PTHPMA (or another hydrophobic polymer which hydrolyzes to form a hydrophilic material), cross-linking agent, and a photoacid generator (PAG) in a pattern lying inside the two-dimensional layout of the channels. After all layers are printed, flood exposure of the entire substrate to UV radiation releases acid from the PAG which hydrolyzes PTHPMA to form hydrophilic poly(methacrylic acid) PMAA, thereby rendering the PTHPMA regions hydrophilic. The layers of these now-hydrophilic patterned regions together define the microfluidic channels. The cross-linking agent (e.g., triallyl isocyanurate TAIC) forms covalent cross-links between the two polymer phases.

CROSS-REFERENCE TO RELATED APPLICATION

This patent application is a divisional application of pending U.S.patent application Ser. No. 13/611,135, filed Sep. 12, 2012, entitled“THERMALLY CROSS-LINKABLE PHOTO-HYDROLYZABLE INKJET PRINTABLE POLYMERSFOR MICROFLUIDIC CHANNELS”, which is hereby incorporated herein byreference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of Invention

The present invention relates in general to the field of microfluidics.More particularly, the present invention relates to using thermallycross-linkable photo-hydrolyzable inkjet printable polymers and inkjetprinting to fabricate one or more microfluidic channels layer-by-layerin a substrate body.

2. Background Art

The field of microfluidics emerged in the 1980s and has enabled thedevelopment of many microscale technologies, including DNA chips,lab-on-a-chip devices, and precision inkjet printing. Microfluidicsprovides the ability to deliver nanoliter and picoliter volumes ofliquids by direct application, such as inkjet printing, or viacontinuous flow through microfluidic channels. Unfortunately, thecurrent process for the creation of three-dimensional microfluidicchannels, i.e., the 2-photon writing process, is expensive and extremelycomplex.

The current 2-photon writing process involves the application of anacid-hydrolyzable polymer brush, poly(tetrahydropyranyl methacrylate)(PTHPMA), onto a glass surface. Interstitial spaces are filled in viaspin coating with a mixture of a photoacid generator (PAG), asensitizer, and a copolymer of methyl methacrylate and poly(ethyleneglycol) methylether methacrylate. Once the mixture has been spin coatedonto the glass surface, a pulsed laser source (e.g., a Ti-sapphirefemtosecond laser) is used to effectively carve out a channel of acid inthe PTHPMA. The pulsed laser source is precisely focused and rasteredthrough the PTHPMA in a pattern that defines the channel. This resultsin localized 2-photon generation of acid (i.e., the PAG is exposedwithin localized regions of the PTHPMA and releases acid only withinthose regions) in the PTHPMA. A 2-photon writing process is required tomaintain the necessary spatial resolution (otherwise, the PAG would beexposed throughout the entire thickness of the PTHPMA and release acideverywhere). The photoacid hydrolyzes the PTHPMA during heating, forminghydrophilic poly(methacrylic acid) (PMAA) in the form of athree-dimensional hydrophilic channel traveling through a hydrophobicsubstrate. The 2-photon writing process requires precise calibration andalignment of one or more femtosecond lasers, which is costly anddifficult to execute. An example of a 2-photon writing process isdisclosed in Lee et al., “Multiphoton Writing of Three-DimensionalFluidic Channels within a Porous Matrix”, Journal of the AmericanChemical Society, Vol. 131, No. 32, 2009, pages 11294-11295, publishedon Web Jul. 28, 2009, which is hereby incorporated herein by referencein its entirety.

Therefore, a need exists for an enhanced mechanism for fabricating oneor more microfluidic channels in a substrate body.

SUMMARY OF THE INVENTION

According to some embodiments of the present invention, inkjet printingand thermally cross-linkable photo-hydrolyzable inkjet printablepolymers are used to print microfluidic channels layer-by-layer on asubstrate. In one embodiment, for each layer, an inkjet head depositsdroplets of a mixture of a hydrophobic polymer and a cross-linking agentin a pattern lying outside a two-dimensional layout of the channels, andanother inkjet head deposits droplets of a mixture ofpoly(tetrahydropyranyl methacrylate) PTHPMA (or another hydrophobicpolymer which hydrolyzes to form a hydrophilic material), across-linking agent, and a photoacid generator (PAG) in a pattern lyinginside the two-dimensional layout of the channels. After all layers areprinted, flood exposure of the entire substrate to UV radiation releasesacid from the PAG which hydrolyzes PTHPMA to form hydrophilicpoly(methacrylic acid) PMAA, thereby rendering the PTHPMA regionshydrophilic. The layers of these now-hydrophilic patterned regionstogether define the microfluidic channels. The cross-linking agent(e.g., triallyl isocyanurate TAIC) forms covalent cross-links betweenthe polymer matrix and the discrete channels printed to form themicrofluidic channels. By crosslinking these two polymer phases, phaseseparation is avoided and well defined microfluidic channels aremaintained.

BRIEF DESCRIPTION OF THE DRAWINGS

The preferred exemplary embodiments of the present invention willhereinafter be described in conjunction with the appended drawings,where like designations denote like elements.

FIG. 1 is a block diagram illustrating an apparatus for fabricating oneor more microfluidic channels in a substrate body using a thermallycross-linkable photo-hydrolyzable inkjet printable polymer in accordancewith some embodiments of the present invention.

FIG. 2 is a block diagram illustrating an exemplary three-dimensionalinkjet printing unit suitable for use in the apparatus of FIG. 1.

FIG. 3 includes a block diagram illustrating an exemplary applicationfor microfluidic channels fabricated layer-by-layer in a substrate bodyin accordance with some embodiments of the present invention, whereinthe microfluidic channels connect a sample inlet area to a plurality ofsensing areas and a reference area. FIG. 3 also includes a sectionaldiagram illustrating a cross-section of one of the microfluidic channelsfabricated layer-by-layer in the substrate body using a thermallycross-linkable photo-hydrolyzable inkjet printable polymer in accordancewith some embodiments of the present invention.

FIG. 4 is a flow diagram illustrating a method of fabricating one ormore microfluidic channels in a substrate body using a thermallycross-linkable photo-hydrolyzable inkjet printable polymer in accordancewith some embodiments of the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

1. Overview

In accordance with some embodiments of the present invention, inkjetprinting and thermally cross-linkable photo-hydrolyzable inkjetprintable polymers are used to print microfluidic channelslayer-by-layer on a substrate. In one embodiment, for each layer, aninkjet head deposits droplets of a mixture of a hydrophobic polymer anda cross-linking agent in a pattern lying outside a two-dimensionallayout of the channels, and another inkjet head deposits droplets of amixture of poly(tetrahydropyranyl methacrylate) PTHPMA (or anotherhydrophobic polymer which hydrolyzes to form a hydrophilic material), across-linking agent, and a photoacid generator (PAG) in a pattern lyinginside the two-dimensional layout of the channels. After all layers areprinted, flood exposure of the entire substrate to UV radiation releasesacid from the PAG which hydrolyzes PTHPMA to form hydrophilicpoly(methacrylic acid) PMAA, thereby rendering the PTHPMA regionshydrophilic. The layers of these now-hydrophilic patterned regionstogether define the microfluidic channels. The cross-linking agent(e.g., triallyl isocyanurate TAIC) forms covalent cross-links betweenthe polymer matrix and the discrete channels printed to form themicrofluidic channels. By crosslinking these two polymer phases, phaseseparation is avoided and well defined microfluidic channels aremaintained.

2. Detailed Description

FIG. 1 is a block diagram illustrating an apparatus 100 for fabricatingone or more microfluidic channels in a substrate body in accordance withsome embodiments of the present invention. The microfluidic channelfabricating apparatus 100 includes a three-dimensional inkjet printingunit 110 and a data processing unit, such as a computer system 120.Preferably, as illustrated in FIG. 1, the three-dimensional (3D) inkjetprinting unit 110 and the data processing unit are provided as separateentities. However, those skilled in the art will appreciate that thedata processing unit and the 3D inkjet printing unit may be integratedinto a single entity.

The 3D inkjet printing unit 110, an example of which is described inmore detail below with reference to FIG. 2, typically includes anenclosure (e.g., 201 shown in FIG. 2) having an access or opening (notshown), as well as a print bed (e.g., 202 shown in FIG. 2) accessiblethrough the opening. A substrate, such as a silica substrate (e.g., 204shown in FIG. 2), rests on the print bed. While the present inventionwill be discussed in terms of fabricating one or more microfluidicchannels on a silica substrate, it should be understood that thisinvention can be used to fabricate one or more microfluidic channels ona variety of substrates, including semiconductor wafers, microelectronicchips, glass, metal, polymer, plastic, paper, etc.

The 3D inkjet printing unit 110 also includes one or more thermallycross-linkable photo-hydrolyzable inkjet printable polymers 112 (e.g., amixture of PTHPMA (or another hydrophobic polymer which hydrolyzes toform a hydrophilic material), a cross-linking agent, and a photoacidgenerator, as described below) that is used to print one or moremicrofluidic channels layer-by-layer on the substrate.

The 3D inkjet printing unit 110 may be a modified version of aconventional 3D inkjet printer. Typically, conventional 3D inkjetprinters are used for rapid prototyping. An object to be prototyped isbuilt layer-by-layer in a conventional 3D inkjet printer from many thincross-sections of a 3D model of the object. An example of a suitableconventional 3D inkjet printer is the ZPrinter, available from ZCorporation, Burlington, Mass. Software is used to slice a 3D model(typically, a 3D CAD model) of the object to be prototyped into thincross-sections that are fed into the conventional 3D inkjet printer. Aninkjet printing head in the conventional 3D inkjet printer moves acrossa bed of powder (typically, plaster or resins) and selectively depositsa liquid binding material in the shape of a first of the thincross-sections. Another layer of powder is then spread across theprevious layer of bound and unbound powder, and the process is repeatedone layer at a time until every layer is printed.

In accordance with an embodiment of the present invention, the 3D inkjetprinting unit 110 is provided by modifying existing hardware, i.e., theinkjet printing heads in a conventional 3D inkjet printer may bemodified to deposit a stream of droplets each having a suitable volume(e.g., approximately 500-2000 femtoliters, as described below) and of asuitable material, such as the thermally cross-linkablephoto-hydrolyzable inkjet printable polymer 112, on a suitable substrate(e.g., a silicate, as described below) in lieu of depositing the liquidbinding material on the powder. In accordance with another embodiment ofthe present invention, instead of modifying existing hardware, the 3Dinkjet printing unit 110 may be provided as a new apparatus.

The computer system 120 is largely conventional except that it includesa modified version of conventional 3D printing software 140 that(preferably, using a microfluidic channel data file 142) performs thefunctions as further described below with reference to FIG. 4. Forexample, the computer system 120 may be a PC. However, those skilled inthe art will appreciate that some aspects of the present invention mayapply equally to any computer system, regardless of whether the computersystem is a complicated multi-user computing apparatus, a PC, or anembedded control system. As shown in FIG. 1, the computer system 120comprises one or more processors 122 and a main memory 124. These systemcomponents, as well as other conventional system components such as ahard disk drive, CD-ROM drive, and a network interface (not shown), areinterconnected through a system bus 126.

A data bus 130 couples the 3D inkjet printing unit 110 to the computersystem 120. Preferably, the 3D inkjet printing unit 110 and the computersystem 120 can provide digital data to each other on the bus 130,through an existing digital I/O port such as an RS-232C serial port orUSB port of the computer system 120. Appropriate control busses may alsoconnect the computer system 120 to the 3D inkjet printing unit 110 in amanner well known in the art.

Any such connections (e.g., a data bus, control busses, etc.) betweenthe 3D inkjet printing unit 110 and the computer system 120 are moregenerally referred to herein as a “network connection” (e.g., 260 shownin FIG. 2).

In the embodiment illustrated in FIG. 1, the 3D printing software 140and the microfluidic channel data file 142 reside in the main memory124. In accordance with some embodiments of the present invention, the3D printing software 140 (preferably, using the microfluidic channeldata file 142) performs the functions as further described below withreference to FIG. 4.

The 3D printing software 140 may be, for example, a modified version ofconventional 3D printing software. An example of suitable conventional3D printing software is ZPrint software, available from Z Corporation,Burlington, Mass. ZPrint software is a tool for preparing CAD files foroptimal printing on Z Corporation 3D Printers. Any such suitableconventional 3D printing software may be modified to perform thefunctions as further described below with reference to FIG. 4. In thiscase, the so-modified 3D printing software can be sold as an integralpart of a new apparatus or as a software upgrade to work with existinghardware.

The microfluidic channel data file 142 preferably is a three-dimensionalmodel of the one or more microfluidic channels (e.g., 310 shown in FIG.3) and/or surrounding structure. For example, the microfluidic channeldata file 142 may be a 3D CAD file. Preferably, the 3D printing software140 imports the microfluidic channel data file 142 and slices thethree-dimensional model of the one or more microfluidic channels and/orsurrounding structure into thin cross-sectional slices. Thesecross-sectional slices are sent from the computer system 120 to the 3Dinkjet printing unit 110 over the data bus 130.

At this point, it is important to note that while the description aboveis in the context of a fully functional computer system, those skilledin the art will appreciate that the 3D printing software 140, as well asother software entities described herein (e.g., the microfluidic channeldata file 142) may be distributed as an article of manufacture (alsoreferred to herein as a “computer program product”) in a variety offorms, and the claims extend to all suitable types of computer-readablemedia used to actually carry out the distribution, including recordabletype media such as floppy disks, CD-RWs, CD-ROMs (e.g., CD-ROM 150 inFIG. 1) and DVD-ROMs.

FIG. 2 is a block diagram illustrating an exemplary 3D inkjet printingunit 200 suitable for use as the 3D inkjet printing unit 110 of FIG. 1.Those skilled in the art will appreciate, however, that the particular3D inkjet printing unit 200 illustrated in FIG. 2 is exemplary and thata 3D inkjet printing unit used in accordance with some embodiments ofthe present invention may take many other forms. For example, a 3Dinkjet printing unit used in accordance with some embodiments of thepresent invention may include an alternative x-y plane drive mechanismand/or an alternative z-axis drive mechanism in lieu of those mechanismsillustrated in FIG. 2.

The 3D inkjet printing unit 200 includes an enclosure 201, a print bed202 (on which rests a substrate 204), at least two inkjet print heads(e.g., a first inkjet head 206 and a second inkjet head 208), an x-yplane drive mechanism 210, and a z-axis drive mechanism 212. The x-yplane drive mechanism 210 produces relative movement between the inkjetheads 206, 208 and the substrate 204 in an x-y plane of the substrate,i.e., parallel to the surface of the print bed 202. The z-axis drivemechanism 212 produces relative motion between the inkjet heads 206, 208and the substrate 204 in a z-direction of the substrate, i.e.,perpendicular to the surface of the print bed 202.

The x-y plane drive mechanism 210, which is conventional, includes ahead carriage 214, a head carriage guide rail 216, a pair of y-stageblocks 218, 220, a head carriage drive mechanism 222, a pair of y-stageguide rails 224, 226, two pair of y-stage guide rail mounts 228, 230,232, 234, and a y-stage drive mechanism 236. The inkjet heads 206, 208are mounted on the head carriage 214, which is moved on the headcarriage guide rail 216 between the y-stage block (left) 218 and they-stage block (right) 220 by the head carriage drive mechanism 222.Typically, the head carriage drive mechanism 222 drives the headcarriage 214 in the x-direction with sufficient precision using a servocontrolled stepper motor/belt arrangement (not shown). One skilled inthe art will appreciate, however, that any suitable conventional drivemechanism may be used, such as a servo controlled stepper motor/leadscrew arrangement.

The y-stage blocks 218, 220 are moved on the y-stage guide rails 224,226 between y-stage guide rail mounts (upper) 230, 234 and y-stage guiderail mounts (lower) 228, 232 by the y-stage drive mechanism 236. Thehead carriage 214, the head carriage guide rail 216 and the headcarriage drive mechanism 222 move along with the y-stage blocks 218,220. Typically, the y-stage drive mechanism 236 drives the y-stageblocks 218, 220 (and, by extension, the head carriage 214) in they-direction with sufficient precision using a servo controlled steppermotor/belt arrangement (not shown). One skilled in the art willappreciate, however, that any suitable conventional drive mechanism maybe used, such as a servo controlled stepper motor/lead screwarrangement.

The z-axis drive mechanism 212, which is conventional, includes theprint bed 202 and a print bed drive mechanism 238. Preferably, the printbed 202 includes one or more clamps (not shown) to secure the substrate204 to the print bed 202. Typically, the print bed drive mechanism 238drives the print bed 202 in the z-direction with sufficient precisionusing a servo controlled stepper motor/belt arrangement (not shown). Oneskilled in the art will appreciate, however, that any suitableconventional drive mechanism may be used, such as a servo controlledstepper motor/lead screw arrangement.

The particular configuration of the inkjet heads 206, 208 illustrated inFIG. 2 is exemplary and for purposes of illustrating embodiments of thepresent invention and, hence, the particular configuration illustratedtherein is not limiting. For example, in the embodiment illustrated inFIG. 2, the inkjet heads 206, 208 are moved together by the x-y planedrive mechanism 210. In alternative embodiment, the inkjet heads 206,208 may be moved independently of each other by an alternative x-y planedrive mechanism.

The particular configuration of each drive mechanism 210, 212illustrated in FIG. 2 is exemplary and for purposes of illustratingembodiments of the present invention and, hence, the particularconfiguration illustrated therein is not limiting. For example, in theembodiment illustrated in FIG. 2, the x-y plane drive mechanism 210moves the head carriage 214 in the y-direction. In an alternativeembodiment, the x-y plane drive mechanism may move the print bed 202 inthe y-direction or may turn a print roller (not shown). This latteralternative embodiment requires that the substrate 204 is sufficientlyflexible for routing over the print roller in a manner analogous topaper routed over a print roller in a conventional inkjet printer. Also,in the embodiment illustrated in FIG. 2, the z-axis drive mechanism 212moves the print bed 202 in the z-direction. In an alternativeembodiment, the z-axis drive mechanism may move the head carriage 214 inthe z-direction.

Preferably, each of the inkjet heads 206, 208 is integrated into amodified version of a conventional inkjet cartridge (not shown). Aconventional inkjet cartridge typically integrates an inkjet head,electronics associated with the inkjet head, and contact pads forelectrically connecting the inkjet cartridge to the inkjet printingunit. In addition, a conventional inkjet cartridge typicallyincorporates a reservoir containing ink. In accordance with someembodiments of the present invention, a suitable material for formingthe one or more microfluidic channels or the surrounding structure isprovided in the reservoir in lieu of ink. Preferably, each inkjetcartridge is mounted to the head carriage 214 in a removable fashion andthe head carriage 214 includes contact pads (not shown) for mating withcorresponding contact pads of each inkjet cartridge.

In accordance with some embodiments of the present invention, the inkjethead 206 deposits a mixture of one or more hydrophobic polymers (e.g.,poly(tetrahydropyranylmethacrylate) also known as “PTHPMA”, poly(methylmethacrylate) also known as “PMMA”, polystyrene, polyisobutylene, and/orany other suitable conventional hydrophobic polymer(s) known to thoseskilled in the art) and one or more suitable cross-linking agents (e.g.,triallyl isocyanurate also known as “TAIC” or any other suitableconventional cross-linking agent known to those skilled in the art) in astream of droplets each having a volume of approximately 500-2000femtoliters on the surface of the substrate 204. Also, in accordancewith some embodiments of the present invention, the inkjet head 208deposits a mixture of one or more hydrophobic polymers containing ahydrolyzable group (e.g., PTHPMA, PMMA, and/or any other suitableconventional hydrophobic polymer(s) known to those skilled in the artwhich hydrolyzes to form a hydrophilic material), one or more suitablecross-linking agents (e.g., triallyl isocyanurate also known as “TAIC”or any other suitable conventional cross-linking agent known to thoseskilled in the art), and one or more photoacid generators (e.g.,triphenylsulfonium hexafluorotriflate, (4-octyloxy-phenyl)phenyliodonium hexafluoroantimonate, and/or any other suitableconventional photoacid generator(s) known to those skilled in the art)in a stream of droplets each having a volume of approximately 500-2000femtoliters on the surface of the substrate 204. The mixture depositedby the inkjet head 208 corresponds to the thermally cross-linkablephoto-hydrolyzable inkjet printable polymer 112 of FIG. 1. The patternsin which the inkjet heads 206, 208 deposit their respective droplets,layer-by-layer, to form the one or more microfluidic channels and thesurrounding structure, are discussed below with reference to FIGS. 3 and4.

In general, the hydrophobic polymer in the mixture deposited by theinkjet head 206 may be the same or different than the hydrophobicpolymer in the mixture deposited by the inkjet head 208. The hydrophobicpolymer in the mixture deposited by the inkjet head 208 must contain ahydrolyzable group (i.e., the hydrophobic polymer in this mixture issubsequently hydrolyzed when UV radiation from flood exposure of theentire substrate releases acid from the PAG in this mixture whichhydrolyzes the hydrophobic polymer in this mixture to form a hydrophilicmaterial that defines the microfluidic channels). However, thehydrophobic polymer in the mixture deposited by the inkjet head 206 neednot contain a hydrolyzable group (i.e., the hydrophobic polymer in thismixture is maintained as a hydrophobic material that defines the polymermatrix surrounding the microfluidic channels).

The cross-linking agent in the mixture deposited by the inkjet head 206and the cross-linking agent in the mixture deposited by the inkjet head208 form covalent cross-links between the polymer matrix and thediscrete channels printed to form the microfluidic channels. Bycrosslinking these two polymer phases, phase separation is avoided andwell defined microfluidic channels are maintained. In general, thecross-linking agent in the mixture deposited by the inkjet head 206 maybe the same or different than the cross-linking agent in the mixturedeposited by the inkjet head 208. Suitable cross-linking agents aremulti-functional thermally cross-linkable monomers that copolymerizewith both the hydrophobic polymer in the mixture deposited by the inkjethead 206 and the hydrophobic polymer in the mixture deposited by theinkjet head 208 to form covalent cross-links between the hydrophobicpolymer in the mixture deposited by the inkjet head 206 and thehydrophobic polymer deposited between the inkjet head 208 when subjectedto heat. That is, the covalent cross-links extend across the interfacebetween these mixtures. Suitable cross-linking agents include, but arenot limited to, TAIC, diallyl itaconate, allyl methacrylate, allylpentaerythritol, N,N′-methylenebis(acrylamide), trimethylolpropanetrimethacrylate, 1,3-butylenegylycol dimethacrylate, polyethyleneglycoldiacrylate, polyethyleneglycol dimethacrylate, ethyleneglycoldimethacrylate, diethyleneglycol divinyl ether, tetraethyleneglycoldiacrylate, and the like. In addition, a thermal initiator may be usedto facilitate curing of the monomers listed above. Suitable thermalinitiators include, but are not limited to, AIBN, BPO and other freeradical thermal initiators.

In accordance with some embodiments of the present invention, themixture deposited by the inkjet head 206 typically contains <10 wt % ofTAIC (and/or one or more other cross-linking agents). The remainder ofthe mixture preferably consists of PTHPMA (and/or one or more otherhydrophobic polymers). Preferably, the mixture deposited by the inkjethead 206 contains 0.01 to 5 wt % of TAIC (and/or one or more othercross-linking agents). More preferably, the mixture deposited by theinkjet head 206 contains 2 to 5 wt % of TAIC (and/or one or more othercross-linking agents).

In accordance with some embodiments of the present invention, themixture deposited by the inkjet head 208 typically contains <2 wt % ofphotoacid generator (PAG). The remainder of the mixture preferablyconsists of PTHPMA (and/or one or more other hydrophobic polymers whichhydrolyze to form hydrophilic materials) and TAIC (and/or one or moreother cross-linking agents). Preferably, the mixture deposited by theinkjet head 208 contains 0.01 to 5 wt % of photoacid generator (PAG).More preferably, the mixture deposited by the inkjet head 208 contains0.1 to 5 wt % of photoacid generator (PAG). Most preferably, the mixturedeposited by the inkjet head 208 contains 0.2 to 1 wt % of photoacidgenerator (PAG).

Also, in accordance with some embodiments of the present invention, themixture deposited by the inkjet head 208 typically contains <10 wt % ofTAIC (and/or one or more other cross-linking agents). The remainder ofthe mixture preferably consists of PTHPMA (and/or one or more otherhydrophobic polymers which hydrolyze to form hydrophilic materials) andPAG. Preferably, the mixture deposited by the inkjet head 208 contains0.01 to 5 wt % of TAIC (and/or one or more other cross-linking agents).More preferably, the mixture deposited by the inkjet head 208 contains 2to 5 wt % of TAIC (and/or one or more other cross-linking agents).

As mentioned above, in accordance with some embodiments of the presentinvention each droplet has a volume of approximately 500-2000femtoliters. An example of a suitable inkjet head is the Multi-layerActuator Head (MACH), commercially available from Seiko EpsonCorporation, Nagano, Japan. As described in an article to Ozawa et al.,“Development of a Femtoliter Piezo Ink-jet Head for high resolutionprinting”, Society for Imaging Science and Technology, NIP23 and DigitalFabrication 2007, Final Program and Proceedings, pages 898-901, the MACHinkjet head is capable of producing droplets as small as 1.5 picoliters.(1 picoliters=1000 femtoliters). The Ozawa et al. article, which alsodescribes an inkjet head capable of producing droplets as small as400-500 femtoliters, is hereby incorporated herein by reference in itsentirety. Generally, droplet volumes at the lower end of theapproximately 500-2000 femtoliters range are more preferred. A dropletvolume of approximately 500 femtoliters is most preferred.

As reported in the Ozawa et al. article, a 500 femtoliter dropletcorresponds to a 10 μm droplet diameter and a 20 μm dot diameter. Thatis, a droplet that has a diameter of 10 μm in flight produces, afterlanding on the substrate, a dot approximately twice that size (actually,the dot diameter varies somewhat depending on a number of factors suchas surface wetting).

Preferably, the 3D inkjet printing unit 200 includes a heat source 239,which (as further discussed below with reference to FIG. 4) is capableof heating the substrate 204 so that the cross-linking agent in each ofthe mixtures deposited by the inkjet heads 206, 208 copolymerizes withthe hydrophobic polymer in each of these mixtures. For example, the heatsource 239 may be a resistive coil heating element lying atop orembedded within the print bed 202.

Preferably, the 3D inkjet printing unit 200 also includes a UV lightsource 240, which (as further discussed below with reference to FIG. 4)is capable of exposing the substrate 204 and rendering a hydrophobicpolymer hydrophilic. For example, ultraviolet light from the lightsource 240 may be used to convert hydrophobic PTHPMA (i.e., droplets ofa mixture deposited on the substrate 204 by the inkjet head 208containing the hydrophobic PTHPMA, a cross-linking agent, and aphotoacid generator) to hydrophilic PMAA.

FIG. 3 includes a block diagram illustrating an exemplary applicationfor microfluidic channels fabricated layer-by-layer in a substrate body300 in accordance with some embodiments of the present invention,wherein a plurality of microfluidic channels 310 connect a sample inletarea 312 to a plurality of sensing areas 314, 316, 318 and a referencearea 320.

The particular microfluidic channel application illustrated in FIG. 3 isexemplary and for purposes of illustrating some embodiments of thepresent invention and, hence, the particular microfluidic channelapplication illustrated therein is not limiting. The particularmicrofluidic channel application illustrated in FIG. 3 is based on anarticle to Abe et al., “Inkjet-Printed Microfluidic MultianalyteChemical Sensing Paper”, Analytical Chemistry, Vol. 80, No. 18, 2008,pages 6928-6934, published on Web Aug. 13, 2008, which is herebyincorporated herein by reference in its entirety. The three-dimensionalhydrophilic microfluidic patterns (550 μm-wide flow channels) disclosedin this article are created by inkjet etching and are open at the topand, therefore, are prone to leak if overturned or suffer contaminationthrough interaction with the environment. In accordance with someembodiments of the present invention, the one or more microfluidicchannels fabricated in the substrate body are surrounded by hydrophobicmaterial and, therefore, are much less likely to leak or becomecontaminated.

In the particular microfluidic channel application illustrated in FIG.3, the sensing areas 314, 316 and 318 contain “chemical sensing inks”that allow for the simultaneous determination of pH (pH-responsive ink),total protein (protein-sensitive ink), and glucose (glucose-sensitiveink) for urine analysis. The “chemical sensing inks” include suitableconventional chemical reagents for colorimetric analytic assay. Duringuse, a urine sample is initially placed into the sample inlet area 312.From the sample inlet area 312, the urine sample flows through themicrofluidic channels 310 via capillary action to the sensing areas 314,316 and 318 and the reference area 320.

FIG. 3 also includes a sectional diagram illustrating a cross-section ofone of the microfluidic channels 310 fabricated layer-by-layer in thesubstrate body 300 in accordance with some embodiments of the presentinvention. The microfluidic channel 310 and a surrounding structure 350are fabricated layer-upon-layer starting with a first layer comprising afirst mixture (e.g., PTHPMA and TAIC) in region 350-1 and a secondmixture (e.g., PTHPMA, TAIC, and a photoacid generator) in region 310-1deposited by the inkjet heads as a stream of droplets on the substrate204 in patterns according to a first cross-sectional slice computed bythe 3D printing software. The first mixture corresponds to the mixturedeposited by the inkjet head 206 of FIG. 2, and the second mixturecorresponds to mixture deposited by the inkjet head 208 of FIG. 2. Thesecond mixture also corresponds to the thermally cross-linkablephoto-hydrolyzable inkjet printable polymer 112 of FIG. 1. Next, asecond layer comprising the first mixture in region 350-2 and the secondmixture in region 310-2 is deposited by the inkjet heads as a stream ofdroplets on the first layer in patterns according to a secondcross-sectional slice computed by the 3D printing software. The processis repeated layer-upon-layer. The twelfth layer is the last to containthe second mixture in region 310-12. The thirteenth, fourteenth, andfifteenth layers contain only the first mixture in regions 350-13,350-14, and 350-15. The substrate body 300 is heated so that thecross-linking agent in each of the mixtures copolymerizes with thehydrophobic polymer in each of the mixtures. In other words, thecross-linking agent in each of the mixtures forms covalent cross-linksbetween the microfluidic channels 310 and the surrounding structure 350.The microfluidic channel 310 is developed by flood exposure of thesubstrate body 300 to UV light, which releases acid from the photoacidgenerator in the second mixture deposited in regions 310-1 through310-12, which hydrolyzes PTHPMA to form PMMA, thereby rendering thehydrophobic PTHPMA within these regions hydrophilic. The surface of thesubstrate 204 is preferably hydrophobic so that the microfluidic channel310 is surrounded by hydrophobic material (i.e., the microfluidicchannel 310 is enclosed by surrounding structure 350 and the substrate204) to minimize leaks and contamination.

By crosslinking the two polymer phases (i.e., hydrophilic microfluidicchannel 310 and hydrophobic surrounding structure 350), phase separationis avoided and well defined microfluidic channels 310 are maintained.

In the embodiment illustrated in FIG. 3, hydrophilic channels arecreated in a hydrophobic matrix. One skilled in the art will appreciate,however, that the opposite is possible in accordance with the presentinvention to create hydrophobic channels in a hydrophilic matrix.

Preferably, the thickness (i.e., in z-direction) of each 2D layer (e.g.the first layer comprising hydrophobic material in region 350-1 andhydrophilic material in region 310-1) is approximately 10 nm to severalhundred microns, and the thickness (i.e., in z-direction) of theresulting 3D structure (e.g., the substrate body) would vary dependingon the number and the size of the microfluidic channels being created.The resulting 3D structure could be anywhere from several hundrednanometers to virtually any size.

The inkjet heads may deposit the droplets using a single piezopulse ormultiple piezopulses per dot produced. This parameter may be used incontrolling the thickness of each 2D layer, along with the dropletvolume. The droplets at the lower end of the approximately 500-2000femtoliters range require an extremely small dot pitch (distance betweendots) to bridge the space between the dots.

The particular configuration of the microfluidic channel 310 illustratedin FIG. 3 is exemplary and for purposes of illustrating some embodimentsof the present invention and, hence, the particular configurationillustrated therein is not limiting. For example, the cross-sectionalprofile of the microfluidic channel may be a shape other than circular,such as square or rectangular. Also, a plurality of microfluidicchannels may be stacked (i.e., one atop another).

Additional inkjet heads may print the “chemical sensing inks” of thesensing areas 314, 316 and 318 and the reference area 320. Like themicrofluidic channels 310, these areas may be surrounded by hydrophobicmaterial to minimize leaks and contamination. Similarly, the sampleinlet area 312 may be prepared using still another inkjet head.

As will be appreciated by one skilled in the art, aspects of the presentinvention may be embodied as a composition, apparatus, method orcomputer program product. Accordingly, aspects of the present inventionmay take the form of an entirely hardware embodiment, an entirelysoftware embodiment (including firmware, resident software, micro-code,etc.), or an embodiment combining software and hardware aspects that mayall generally be referred to herein as a “circuit,” “module” or“system.” Furthermore, aspects of the present invention may take theform of a computer program product embodied in one or more computerreadable medium(s) having computer readable program code embodiedthereon.

Any combination of one or more computer readable medium(s) may beutilized. The computer readable medium may be a computer readable signalmedium or a computer readable storage medium. A computer readablestorage medium may be, for example, but not limited to, an electronic,magnetic, optical, electromagnetic, infrared, or semiconductor system,apparatus, or device, or any suitable combination of the foregoing. Morespecific examples (a non-exhaustive list) of the computer readablestorage medium would include the following: an electrical connectionhaving one or more wires, a portable computer diskette, a hard disk, arandom access memory (RAM) (e.g., memory 124 in FIG. 1), a read-onlymemory (ROM), an erasable programmable read-only memory (EPROM or Flashmemory), an optical fiber, a portable compact disc read-only memory(CD-ROM) (e.g., CD-ROM 150 in FIG. 1), an optical storage device, amagnetic storage device, or any suitable combination of the foregoing.In the context of this document, a computer readable storage medium maybe any tangible medium that can contain, or store a program for use byor in connection with an instruction execution system, apparatus, ordevice.

A computer readable signal medium may include a propagated data signalwith computer readable program code embodied therein, for example, inbaseband or as part of a carrier wave. Such a propagated signal may takeany of a variety of forms, including, but not limited to,electro-magnetic, optical, or any suitable combination thereof. Acomputer readable signal medium may be any computer readable medium thatis not a computer readable storage medium and that can communicate,propagate, or transport a program for use by or in connection with aninstruction execution system, apparatus, or device.

Program code embodied on a computer readable medium may be transmittedusing any appropriate medium, including but not limited to wireless,wireline, optical fiber cable, RF, etc., or any suitable combination ofthe foregoing. Computer program code for carrying out operations foraspects of the present invention may be written in any combination ofone or more programming languages, including an object orientedprogramming language such as Java, Smalltalk, C++ or the like andconventional procedural programming languages, such as the “C”programming language or similar programming languages. The program codemay execute entirely on the user's computer, partly on the user'scomputer, as a stand-alone software package, partly on the user'scomputer and partly on a remote computer or entirely on the remotecomputer or server. In the latter scenario, the remote computer may beconnected to the user's computer through any type of network, includinga local area network (LAN) or a wide area network (WAN), or theconnection may be made to an external computer (for example, through theInternet using an Internet Service Provider).

Aspects of the present invention are described below with reference toflowchart illustrations and/or block diagrams of methods, apparatus(systems) and computer program products according to embodiments of theinvention. It will be understood that each block of the flowchartillustrations and/or block diagrams, and combinations of blocks in theflowchart illustrations and/or block diagrams, can be implemented bycomputer program instructions. These computer program instructions maybe provided to a processor of a general purpose computer (e.g.,processor 122 of computer system 120 in FIG. 1), special purposecomputer, or other programmable data processing apparatus to produce amachine, such that the instructions, which execute via the processor ofthe computer or other programmable data processing apparatus, createmeans for implementing the functions/acts specified in the flowchartsand/or block diagram block or blocks.

These computer program instructions may also be stored in a computerreadable medium that can direct a computer, other programmable dataprocessing apparatus, or other devices to function in a particularmanner, such that the instructions stored in the computer readablemedium produce an article of manufacture including instructions whichimplement the function/act specified in the flowcharts and/or blockdiagram block or blocks. The computer program instructions may also beloaded onto a computer, other programmable data processing apparatus, orother devices to cause a series of operational steps to be performed onthe computer, other programmable apparatus or other devices to produce acomputer implemented process such that the instructions which execute onthe computer or other programmable apparatus provide processes forimplementing the functions/acts specified in the flowcharts and/or blockdiagram block or blocks.

FIG. 4 is a flow diagram illustrating a method 400 of fabricating one ormore microfluidic channels in a substrate body in accordance with someembodiments of the present invention. In the method 400, a first inkjethead prints a first mixture of a hydrophobic polymer and a cross-linkingagent, and a second inkjet head prints a mixture of a cross-linkingagent, a photoacid generator and a hydrophobic polymer that is renderedhydrophilic upon exposure to UV light.

In the method 400, the steps discussed below (steps 405-440) areperformed. These steps are set forth in their preferred order. It mustbe understood, however, that the various steps may occur at differenttimes relative to one another than shown, or may occur simultaneously.Moreover, those skilled in the art will appreciate that one or more ofthe steps may be omitted.

The method 400 begins by placing the substrate on the print bed (step405). The step 405 may be performed manually by a human or automaticallyby the 3D printing software, for example.

Also, the method 400 continues with the 3D printing software developinga two-dimensional layout (i.e., a cross-sectional slice) of the one ormore microfluidic channels layer-by-layer based on a three-dimensionalrepresentation of the one or more microfluidic channels (step 410).During the step 410, the 3D printing software may import themicrofluidic channel data file (e.g., 3D CAD file) and slice thethree-dimensional representation of the one or more microfluidicchannels and surrounding structure into thin cross-sectional slices.These cross-sectional slices may then be sent to the 3D inkjet printingunit.

Generally, the steps 405 and 410 may be performed simultaneously ortheir order reversed.

Next, the method 400 continues with the first inkjet head directing astream of droplets of a first mixture a hydrophobic polymer and across-linking agent at the surface of the substrate as the first inkjethead is moved relative to the substrate in the x-y plane of thesubstrate (step 415). During the step 415, the first mixture isdeposited on the surface of the substrate in a pattern lying outside thetwo-dimensional layout of the one or more microfluidic channels.

Also, the method 400 continues with the second inkjet head directing astream of droplets of a mixture of PTHPMA (or another hydrophobicpolymer which hydrolyzes to form a hydrophilic material), across-linking agent, and a photoacid generator at the surface of thesubstrate as the second inkjet head is moved relative to the substratein the x-y plane of the substrate in a pattern lying inside thetwo-dimensional layout of the one or more microfluidic channels (step420).

Generally, the steps 415 and 420 may be performed simultaneously (if theinkjet heads move independently) or their order reversed.

Next, the method 400 continues with the determination of whether thelayer just printed is the last layer (step 425). The determination ofstep 425 may be made in the 3D printing unit based on thecross-sectional slices received from the 3D printing software.Alternatively, the determination may be made by the 3D printingsoftware, itself.

If it is determined in the step 425 that the layer just printed is notthe last layer, the print bed is moved relative to the inkjet heads inthe z-direction of the substrate (step 430). During the step 430, theprint bed may be moved away from the inkjets heads in the z-direction bya distance corresponding to the deposit depth of the layer justdeposited. Then, the method loops back to the step 415 to print the nextlayer.

If, on the other hand, it is determined in the step 425 that the layerjust printed is the last layer, then the substrate is heated so that thecross-linking agent in each of the mixtures copolymerizes with thehydrophobic polymer in each of the mixtures (step 435). Activation ofthe heat source in the step 435 may be invoked by either the 3D printingunit or by the 3D printing software. Alternatively, the heat source maybe activated manually by a human. The heat source will heat thesubstrate to a suitable temperature for a suitable period of timesufficient to accomplish the cross-linking. Typically, the heat sourcewill heat the substrate to 60 to 90 C for 1 to 15 minutes.

Next, the substrate is exposed to UV light to render the hydrophobicPTHPMA hydrophilic (step 440). Activation of the UV light source in thestep 440 may be invoked by either the 3D printing unit or by the 3Dprinting software. Alternatively, the UV light source may be activatedmanually by a human. Typically, the UV light will penetrate all of thelayers to a sufficient extent to convert the entirety of the hydrophobicpolymer. However, it may be desirable in some cases (e.g., if the totaldepth of the layers is large) to intermittently expose the substratebefore all of the layers are deposited.

After the step 440 is completed, the method ends (step 445).

The flowcharts and block diagrams in the Figures illustrate thearchitecture, functionality, and operation of possible implementationsof compositions, apparatus, methods and computer program productsaccording to various embodiments of the present invention. In thisregard, each block in the flowcharts or block diagrams may represent amodule, segment, or portion of code, which comprises one or moreexecutable instructions for implementing the specified logicalfunction(s). It should also be noted that, in some alternativeimplementations, the functions noted in the block may occur out of theorder noted in the figures. For example, two blocks shown in successionmay, in fact, be executed substantially concurrently, or the blocks maysometimes be executed in the reverse order, depending upon thefunctionality involved. It will also be noted that each block of theblock diagrams and/or flowchart illustrations, and combinations ofblocks in the block diagrams and/or flowchart illustrations, can beimplemented by special purpose hardware-based systems that perform thespecified functions or acts, or combinations of special purpose hardwareand computer instructions.

Embodiments herein may also be delivered as part of a service engagementwith a client corporation, nonprofit organization, government entity,internal organizational structure, or the like. These embodiments mayinclude configuring a computer system to perform some or all of themethods described herein, and deploying software, hardware, and webservices that implement some or all of the methods described herein.

One skilled in the art will appreciate that many variations are possiblewithin the scope of the present invention. Thus, while the presentinvention has been particularly shown and described with reference topreferred embodiments thereof, it will be understood by those skilled inthe art that these and other changes in form and details may be madetherein without departing from the spirit and scope of the presentinvention.

What is claimed is:
 1. A method of fabricating one or more microfluidicchannels in a substrate body, comprising the steps of: placing asubstrate on a print bed; directing a stream of droplets of a firstmixture from a first inkjet head at a surface of the substrate, whereinthe first mixture contains a first hydrophobic polymer and a firstcross-linking agent; directing a stream of droplets of a second mixturefrom a second inkjet head at the surface of the substrate, wherein thesecond mixture contains a second hydrophobic polymer, a secondcross-linking agent, and a photoacid generator, and wherein the secondhydrophobic polymer contains a hydrolyzable group and hydrolyzes to forma hydrophilic material; moving the first and second inkjet headsrelative to the substrate in an x-y plane of the substrate, wherein thestep of moving the first and second inkjet heads relative to thesubstrate in the x-y plane of the substrate, for each of a plurality oflayers, includes the steps of: moving the first inkjet head relative tothe substrate so as to deposit droplets of the first mixture on thesurface of the substrate in a first pattern based on a two-dimensionallayout of the one or more microfluidic channels; and moving the secondinkjet head relative to the substrate so as to deposit droplets of thesecond mixture on the surface of the substrate in a second pattern basedon the two-dimensional layout of the one or more microfluidic channels;heating the substrate to copolymerize each of the first cross-linkingagent and the second cross-linking agent with both the first hydrophobicpolymer and the second hydrophobic polymer to form covalent cross-linksbetween the first hydrophobic polymer and the second hydrophobicpolymer; exposing the substrate having the plurality of layers depositedthereon to UV light to render the second hydrophobic polymerhydrophilic.
 2. The method as recited in claim 1, further comprising thestep of: moving the first and second inkjet heads relative to thesubstrate in a z-direction of the substrate, wherein the step of movingthe first and second inkjet heads relative to the substrate in az-direction of the substrate, for each of the plurality of layers,includes the step of: moving the print bed by a predetermined distancein a direction away from the first and second inkjet heads after thedroplets are deposited on the surface of the substrate, wherein thepredetermined distance is the deposit depth of the droplets in thatlayer.
 3. The method as recited in claim 1, wherein the exposing stepcomprises flood exposure of the entire substrate to UV radiation.
 4. Themethod as recited in claim 1, wherein the first and second inkjet headsare piezoelectric inkjet heads configured to deliver droplets having avolume of approximately 500-2000 femtoliters.
 5. The method as recitedin claim 1, wherein the second hydrophobic polymer is selected from agroup consisting of poly(tetrahydropyranyl methacrylate) (PTHPMA),poly(methyl methacrylate) (PMMA), and combinations thereof, and whereinthe second cross-linking agent includes triallyl isocyanurate (TAIC). 6.The method as recited in claim 5, wherein the first hydrophobic polymeris selected from a group consisting of poly(tetrahydropyranylmethacrylate) (PTHPMA), poly(methyl methacrylate) (PMMA), andcombinations thereof, and wherein the first cross-linking agent includestriallyl isocyanurate (TAIC).
 7. The method as recited in claim 5,wherein the first hydrophobic polymer is selected from a groupconsisting of polystyrene, polyisobutylene, and combinations thereof,and wherein the first cross-linking agent includes triallyl isocyanurate(TAIC).
 8. A computer program product for fabricating one or moremicrofluidic channels in a substrate body, the computer program productcomprising: a computer readable storage medium having computer readableprogram code embodied therewith, the computer readable program code whenexecuted by a processor in a digital computing device causes athree-dimensional inkjet printing unit to perform the steps of:directing a stream of droplets of a first mixture from a first inkjethead at a surface of a substrate, wherein the first mixture contains afirst hydrophobic polymer and a first cross-linking agent; directing astream of droplets of a second mixture from a second inkjet head at thesurface of the substrate, wherein the second mixture contains a secondhydrophobic polymer, a second cross-linking agent, and a photoacidgenerator, and wherein the second hydrophobic polymer contains ahydrolyzable group and hydrolyzes to form a hydrophilic material; movingthe first and second inkjet heads relative to the substrate in an x-yplane of the substrate, wherein the step of moving the first and secondinkjet heads relative to the substrate in the x-y plane of thesubstrate, for each of a plurality of layers, includes the steps of:moving the first inkjet head relative to the substrate so as to depositdroplets of the first mixture on the surface of the substrate in a firstpattern based on a two-dimensional layout of the one or moremicrofluidic channels; and moving the second inkjet head relative to thesubstrate so as to deposit droplets of the second mixture on the surfaceof the substrate in a second pattern based on the two-dimensional layoutof the one or more microfluidic channels; heating the substrate so thatthe first cross-linking agent and the second cross-linking agent eachcopolymerizes with both the first hydrophobic polymer and the secondhydrophobic polymer to form covalent cross-links between the firsthydrophobic polymer and the second hydrophobic polymer; exposing thesubstrate having the plurality of layers deposited thereon to UV lightto render the second hydrophobic polymer hydrophilic.